The field of the invention is systems and methods for focused ultrasound. More particularly, the invention relates to systems and methods for controlling the delivery of focused ultrasound.
Focused ultrasound (“FUS”) disruption of the blood-brain barrier (“BBB”) using circulating microbubbles is a field of increasing research with the potential to revolutionize treatment of brain and central nervous system (“CNS”) disorders. The BBB prevents passage of molecules from the vasculature into the brain tissue when the molecules are larger than around five hundred Daltons, thereby significantly reducing the efficacy of pharmaceutical and other agents.
FUS disruption of the BBB has been successfully used to deliver amyloid-beta antibodies, as described by J. F. Jordao, et al., in “Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-Beta Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease,” PLoS One 2010; 5:e10549; large molecule chemotherapy agents, as described by M. Kinoshita, et al., in “Noninvasive Localized Delivery of Herceptin to the Mouse Brain by MRI-Guided Focused Ultrasound-Induced Blood-Brain Barrier Disruption,” Proc. Natl. Acad. Sci. USA, 2006; 103:11719-11723; and other large molecules of clinically relevant size, as described by J. J. Choi, et al., in “Molecules of Various Pharmacologically-Relevant Sizes Can Cross the Ultrasound-Induced Blood-Brain Barrier Opening In Vivo,” Ultrasound Med. Biol., 2010; 36:58-67.
Currently, the greatest limitation for the clinical translation of FUS BBB disruption (“BBBD”) is the lack of a real-time technique for monitoring the delivery of FUS to the subject. Disruption can be evaluated using contrast-enhanced magnetic resonance imaging (“MRI”), but such methods provide insufficient temporal resolution to provide real-time feedback.
The introduction of ultrasound contrast agents, such as microbubble contrast agents, to the brain can be seen as a safety concern, especially when using transcranial FUS. Moreover, the use of ultrasound in the skull cavity has been known to make estimation of in situ pressure magnitudes and distributions more difficult, as described by M. A. O'Reilly, et al., in “The Impact of Standing Wave Effects on Transcranial Focused Ultrasound Disruption of the Blood-Brain Barrier in a Rat Model,” Phys. Med. Biol., 2010; 55:5251-5267. This increased difficulty in pressure estimation when using transcranial ultrasound highlights the need for a real-time technique to monitor the microbubble behavior during FUS induced BBBD.
Studies have been conducted to examine the effects of various acoustic and contrast agent parameters on BBBD in an attempt to identify optimal disruption parameters. For example, see the studies described by F.-Y. Yang, et al., in Quantitative Evaluation of the Use of Microbubbles with Transcranial Focused Ultrasound on Blood-Brain-Barrier Disruption,” Ultrason. Sonochem., 2008; 15:636-643; by N. McDannold, et al., in “Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption,” Ultrasound Med. Biol., 2008; 34:930-937; by R. Chopra, et al., in “Influence of Exposure Time and Pressure Amplitude on Blood-Brain-Barrier Opening using Transcranial Ultrasound Exposures,” ACS Chem. Neurosci., 2010; 1:391-398; and by J. J. Choi, et al., in “Microbubble-Size Dependence of Focused Ultrasound-Induced Blood-Brain Barrier Opening in Mice In Vivo,” IEEE Trans. Biomed. Eng., 2010; 57:145-154.
Other studies have preferred to examine the microbubble emissions during BBBD in order to identify an emissions characteristic that could identify an appropriate treatment endpoint. For example, a sharp increase in harmonic emissions during sonications resulting in successful BBBD has been observed, as described by N. McDannold, et al., in “Targeted Disruption of the Blood-Brain Barrier with Focused Ultrasound: Association with Cavitation Activity,” Phys. Med. Biol., 2006; 51:793-807. In another study, the presence of the fourth and fifth harmonics where observed when BBBD occurred, as described by Y.-S. Tung, et al., in “In Vivo Transcranial Cavitation Threshold Detection During Ultrasound-Induced Blood-Brain Barrier Opening in Mice,” Phys. Med. Biol., 2010; 55:6141-6155. It was observed that these higher harmonics were absent when BBBD was unsuccessful; however, harmonic signal content can arise from the tissue or coupling media, and not just the circulating microbubbles. As a result, these harmonic signal components may not result in the most robust method of controlling treatments.
It would therefore be desirable to provide a system and method for controlling the delivery of ultrasound energy to a subject such that blood-brain barrier disruption can be achieved without injury to the subject.